The present applicants found an optically active compound useful as a pharmaceutical agent having an activity of bone formation and a bone resorption activity, i.e. a prophylactic and therapeutic agent of bone diseases, and have filed a patent application on this compound EP-A-719782, Application Number 95 120444.5!.
As methods of optically resolving a racemic modification, a mixture of optically active compounds, there have been generally employed, on a laboratory scale, and, in very limited cases, on an industrial scale, (1) preferential crystallization from a racemic modification, (2) a diastereomer method using an agent of optical resolution, (3) a fractionating method using a column chromatography packed with an optically active substance, (4) a fractionating method utilizing the stereospecificity of enzymic reaction and (5) a fractionating method using an optically active film.
As examples of norephedrine subjected to optical resolution of optical isomers, descriptions are found in, for example, JPA S60(1985)-224672, JPA S48(1973)-23724 (U.S. Pat. No. 3,966,752), Liebigs Ann. Chem. p.1995 (1982) and EP-A-128684. However, these are nothing more than examples attempted for a certain specific compound. In other words, since no general regularity has been established on the optical resolution of optical isomers, when conducting optical resolution of optical isomers, various methods have to be investigated on respective compounds at the present technical level in the relevant field.
So far, production of an optically active benzothiepin derivative which is a raw material of the above-mentioned optically active compound useful as a prophylactic and therapeutic agent of bone diseases, especially an optically active 3-benzothiepin-2-carboxylic acid derivative, has been conducted by, for example, allowing a racemic isomer of 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carb oxylic acid to react with methyl mandelate, followed by recrystallization utilizing the difference in solubilities of diastereomers of the resulting ester derivative. This method, however, requires the formation of ester linkage and re-cleavage, and produces a relatively large amount of undesirable by-products, which requires complicated refining steps resulting in a low yield, thus a number of problems have been left to be solved for realizing the production on an industrial scale.
Circumstances being such as above, development of a method of producing efficiently an optically active benzothiepin derivative, especially (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepi n-2-carboxylic acid, as an optically active form in a substantially pure state, has been desired.
And, since the above-mentioned optically active compound useful as a prophylactic and therapeutic agent of bone diseases varies in its pharmaceutical activity and absorbability (especially oral absorbability), depending on the kind of an optically active form, production of a specific optically active compound which is excellent in a pharmaceutical activity and absorbability is desired. Accordingly, development of a method of producing an optically active benzothiepin derivative which is a raw material for production of the specific optically active compound is desired.